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1.
OxLDL plasma levels in patients with Alzheimer's disease.
Grossi, MF, Carvalho, MDG, Silveira, JN, Gonçalves, GS, Gomes, KB, Bicalho, MA, Silva, IFO
Arquivos de neuro-psiquiatria. 2018;(4):241-246
Abstract
OBJECTIVE The objective of this study was to characterize the conventional lipid profile, oxLDL levels and ApoE polymorphism in patients with Alzheimer's disease (AD) and in elderly individuals without cognitive impairment. METHODS Eighty elderly individuals were selected and the levels of oxLDL were determined using the ELISA kit, and ApoE gene polymorphism was investigated using polymerase chain reaction-restriction fragment length polymorphism. RESULTS Significantly reduced levels of oxLDL were observed in patients with AD compared to the control group. A higher frequency of the ApoE ε4 allele was observed in patients with AD compared to controls. No difference was observed for total cholesterol, HDL-C, and LDL-C levels between the two groups, while triglyceride levels were higher in controls compared with patients with AD. CONCLUSION The data analyzed together did not reveal significant differences in lipid profiles, including oxLDL levels. However, the importance of lipid changes in the genesis of the disease cannot be ruled out. Nevertheless, the ApoE ε4 allele was significantly more frequent in patients with Alzheimer's dementia in agreement with previous findings in the literature, but this genetic component did not change the levels of oxLDL.
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2.
Antecedents of Soft Drusen, the Specific Deposits of Age-Related Macular Degeneration, in the Biology of Human Macula.
Curcio, CA
Investigative ophthalmology & visual science. 2018;(4):AMD182-AMD194
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Abstract
AMD pathobiology was irreversibly changed by the recent discovery of extracellular cholesterol-containing deposits in the subretinal space, between the photoreceptors and retinal pigment epithelium (RPE), called subretinal drusenoid deposits (SDDs). SDDs strikingly mirror the topography of rod photoreceptors in human macula, raising the question of whether an equivalent process results in a deposition related to foveal cones. Herein we propose that AMD's pathognomonic lesion-soft drusen and basal linear deposit (BLinD, same material, diffusely distributed)-is the leading candidate. Epidemiologic, clinical, and histologic data suggest that these deposits are most abundant in the central macula, under the fovea. Strong evidence presented in a companion article supports the idea that the dominant ultrastructural component is large apolipoprotein B,E-containing lipoproteins, constitutively secreted by RPE. Lipoprotein fatty acids are dominated by linoleate (implicating diet) rather than docosahexaenoate (implicating photoreceptors); we seek within the retina cellular relationships and dietary drivers to explain soft druse topography. The delivery of xanthophyll pigments to highly evolved and numerous Müller cells in the human fovea, through RPE, is one strong candidate, because Müller cells are the main reservoir of these pigments, which replenish from diet. We propose that the evolution of neuroglial relations and xanthophyll delivery that underlie exquisite human foveal vision came with a price, that is, soft drusen and sequela, long after our reproductive years.
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PCSK9: A potential regulator of apoE/apoER2 against inflammation in atherosclerosis?
Bai, XQ, Peng, J, Wang, MM, Xiao, J, Xiang, Q, Ren, Z, Wen, HY, Jiang, ZS, Tang, ZH, Liu, LS
Clinica chimica acta; international journal of clinical chemistry. 2018;:192-196
Abstract
Atherosclerosis is characterized by chronic inflammation and lipid accumulation in arterial walls, resulting in several vascular events. Proprotein convertase subtilisin kexin 9 (PCSK9), a serine protease, has a pivotal role in the degradation of hepatic low-density lipoprotein receptor (LDLR). It can increase plasma concentrations of low-density lipoprotein cholesterol and affect lipid metabolism. Recently, PCSK9 has been found to accelerate atherosclerosis via mechanisms apart from that involving the degradation of LDLR, with an emerging role in regulating the inflammatory response in atherosclerosis. Apolipoprotein E receptor 2 (apoER2), one of the LDLR family members expressed in macrophages, can bind to its ligand apolipoprotein E (apoE), exhibiting an anti-inflammatory role in atherosclerosis. Evidence suggests that apoER2 is a target of PCSK9. This review aims to discuss PCSK9 as a potential regulator of apoE/apoER2 against inflammation in atherosclerosis.
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High-density lipoprotein cholesterol, apolipoprotein E and atherogenic index of plasma are associated with risk of chronic kidney disease.
Smajić, J, Hasić, S, Rašić, S
Medicinski glasnik : official publication of the Medical Association of Zenica-Doboj Canton, Bosnia and Herzegovina. 2018;(2):115-121
Abstract
Aim To investigate the association of parameters of lipid profile and estimated glomerular filtration rate (eGFR) p<60 ml/min/1.73m2 calculated by the Modification of Diet in Renal Disease (MDRD) in non-dialysis kidney patients. Methods The observational, case-control study enrolled patients (n=117) recruited from the Nephrological Counselling Centre of the University Clinical Centre Sarajevo and divided into two groups: group 1 eGFR (15-59 mL/min/1.73 m2 ), and group 2 (control) eGFR ≥ 60 mL/min/1.73 m2 . Concentration of lipids, lipoproteins and apolipoproteins was measured, and atherogenic index of plasma (AIP; log(TG/HDLc)) was calculated. Results High density lipoprotein cholesterol (HDLc) and apolipoprotein E (APOE) concentrations in serum were reduced [(1.02 (0.94-1.29) vs 1.15 (1.1-1.4) mmol/L; p=0.009 and 0.035 (0.026-0.04) vs 0.041 (0.034-0.05) g/L; p=0.002, respectively)], while AIP was higher in group 1 than in group 2 (0.19±0.03 vs 0.09±0.04; p=0.013). Values less than 1.09 mmol/L and 0.038 g/L for HDLc and APOE, or higher than 0.165 for AIP (p< 0.05) were associated with the eGFR below 60 ml/min/1.73 m2. The age [OR = 1.1; 95% CI (1.05-1.17)] and AIP [OR = 8.7; 95% CI (1.18- 65.0)] were independent positive predictors, while APOE was a negative predictor of eGFR reduction rate (OR=0.01; 95% CI (0.001-0.033; p<0.001). Conclusion Changes in parameters such as HDLc, APOE and AIP are associated with CKD. The study results imply the need of the AIP calculation as routine laboratory work due to its role along with the age and APOE in the prediction of renal function decline.
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The association between the SLCO1B1, apolipoprotein E, and CYP2C9 genes and lipid response to fluvastatin: a meta-analysis.
Xiang, Q, Zhang, X, Ma, L, Hu, K, Zhang, Z, Mu, G, Xie, Q, Chen, S, Cui, Y
Pharmacogenetics and genomics. 2018;(12):261-267
Abstract
OBJECTIVE The aim of this study was to determine the impact of the SLCO1B1, apolipoprotein E (ApoE), and CYP2C9 genotypes on the lipid-lowering efficacy of fluvastatin. METHODS We performed electronic searches on the PubMed, Embase, and Cochrane Library databases to identify studies published through October 2017. Studies that reported the effect estimates with 95% confidence intervals (CIs) of total cholesterol (TC), triglyceride, low-density lipoprotein (LDL), and high-density lipoprotein were included so that the different genotype categories could be compared. Weighted mean difference (WMD) was used to summarize the effect estimates. RESULTS Six studies, involving a total of 1171 individuals, were included in the final analysis. We noted that the patient carrier SLCO1B1 521TT was associated with greater change in TC (WMD: -2.98; 95% CI: -5.12 to -0.84; P=0.006) and LDL (WMD: -5.58; 95% CI: -10.64 to -0.52; P=0.031) compared with 521TC or CC. Furthermore, the patient carrier ApoE*2/*3 showed more change in high-density lipoprotein compared with ApoE*3/*3 (WMD: 18.76; 95% CI: 8.97-28.55; P<0.001) and ApoE*3/*4 or *4/*4 (WMD: 22.51; 95% CI: 0.98-44.04; P=0.040). Finally, the CYP2C9 genotypes showed no correlation with the effects of fluvastatin on TC, triglyceride, and LDL. CONCLUSION The findings of this study suggested that the SLCO1B1 and ApoE polymorphisms could influence the lipid-lowering effect of fluvastatin, whereas the CYP2C9 genotypes were not associated with the therapeutic effects of fluvastatin.
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Familial Hypertrophic Cardiomyopathy - Identification of cause and risk stratification through exome sequencing.
Biswas, A, Das, S, Kapoor, M, Shamsudheen, KV, Jayarajan, R, Verma, A, Seth, S, Bhargava, B, Scaria, V, Sivasubbu, S, et al
Gene. 2018;:151-156
Abstract
BACKGROUND Hypertrophic Cardiomyopathy (HCM) with variable clinical presentations and heterogeneity is the common cause of sudden cardiac death. Genetic diagnosis is challenging in these complex diseases but exome sequencing as a genetic diagnostic tool provides explainable results. METHODS In a familial Hypertrophic Cardiomyopathy with multigenerational inheritance with apparent phenotype, had a history of sudden death and severe arrhythmia followed by implantation of Implantable cardioverter defibrillator (ICD). Exome sequencing (100×) trailed by effective filtering steps for exome variants on the basis of different parameters, segregated variants are prioritized for the disease and further clinical relevance are evaluated for the variants. RESULTS A rare causal variant in troponin-T gene (TNNT2, NM_000364.3;c.274C > T;p.Arg92Trp) is identified, shared by only affected members, absent in unaffected members and also in 200 unrelated control chromosomes. TNNT2 mutation act as a driver mutation but mutations in other disease-related genes, KCNMB1, LPL, APOE and other biochemical factors provides risk stratification within affected family members. CONCLUSION This study contributes to the role of "rare variants" in complex disease phenotypes and heterogeneity within family and the necessity of whole exome targeted approaches in complex cardiomyopathy, which are known to harbor private mutations.
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Clinical Application of APOE in Alzheimer's Prevention: A Precision Medicine Approach.
Berkowitz, CL, Mosconi, L, Rahman, A, Scheyer, O, Hristov, H, Isaacson, RS
The journal of prevention of Alzheimer's disease. 2018;(4):245-252
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Abstract
Population-attributable risk models estimate that up to one-third of Alzheimer's disease (AD) cases may be preventable through risk factor modification. The field of AD prevention has largely focused on addressing these factors through universal risk reduction strategies for the general population. However, targeting these strategies in a clinical precision medicine fashion, including the use of genetic risk factors, allows for potentially greater impact on AD risk reduction. Apolipoprotein E (APOE), and specifically the APOE ε4 variant, is one of the most well-established genetic influencers on late-onset AD risk. In this review, we evaluate the impact of APOE ε4 carrier status on AD prevention interventions, including lifestyle, nutrigenomic, pharmacogenomic, AD comorbidities, and other biological and behavioral considerations. Using a clinical precision medicine strategy that incorporates APOE ε4 carrier status may provide a highly targeted and distinct approach to AD prevention with greater potential for success.
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Apolipoprotein E-containing high-density lipoprotein (HDL) modifies the impact of cholesterol-overloaded HDL on incident coronary heart disease risk: A community-based cohort study.
Qi, Y, Liu, J, Wang, W, Wang, M, Zhao, F, Sun, J, Liu, J, Zhao, D
Journal of clinical lipidology. 2018;(1):89-98.e2
Abstract
BACKGROUND Experimental studies have shown that cholesterol-overloaded high-density lipoprotein (HDL) can promote the formation of apolipoprotein E (APOE)-containing HDL, a process correcting the atherogenic function of cholesterol-overloaded HDL. OBJECTIVE The objective of the study was to explore whether APOE-containing HDL can attenuate the defective impact of cholesterol-overloaded HDL on the development of coronary heart disease (CHD) in humans. METHODS We measured APOE-HDL cholesterol (APOE-HDLC), HDL cholesterol (HDLC), and HDL particle number in 1112 participants aged 45 to 74 years at baseline in a community-based cohort study. Cholesterol molecules per HDL particle (HDL-C/P ratio) were calculated as the ratio of HDLC to HDL particle number. The ratio of APOE-HDLC to total HDLC (APOE-HDLC/HDLC ratio) was calculated to assess the relative proportion of APOE-HDLC in total HDLC. RESULTS The HDL-C/P ratio was strongly correlated with APOE-HDLC (partial-r: 0.615). Participants with cholesterol-overloaded HDL (indicated by the highest level of the HDL-C/P ratio) had a high APOE-HDLC/HDLC ratio. Baseline cholesterol-overloaded HDL significantly increased the 10-year risk of incident CHD (hazard ratio = 2.42; 95% confidence interval = 1.06-8.32), but this was attenuated by an increased APOE-HDLC/HDLC ratio. Participants with high HDL-C/P ratio and APOE-HDLC/HDLC ratio had a 42% lower risk, whereas those with a high HDL-C/P ratio and low APOE-HDLC/HDLC ratio had a 2.54-fold higher risk, than those with low HDL-C/P ratio and APOE-HDLC/HDLC ratio after multiple adjustments. CONCLUSION Cholesterol-overloaded HDLs are related with increased APOE-containing HDL species. APOE-containing HDL was found to attenuate the impact of cholesterol-overloaded HDL on increased incident CHD risk, suggesting that APOE-containing HDL may correct the dysfunction of cholesterol-overloaded HDL.
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Gene-gene interactions among coding genes of iron-homeostasis proteins and APOE-alleles in cognitive impairment diseases.
Tisato, V, Zuliani, G, Vigliano, M, Longo, G, Franchini, E, Secchiero, P, Zauli, G, Paraboschi, EM, Vikram Singh, A, Serino, ML, et al
PloS one. 2018;(3):e0193867
Abstract
Cognitive impairments of different aetiology share alterations in iron and lipid homeostasis with mutual relationships. Since iron and cholesterol accumulation impact on neurodegenerative disease, the associated gene variants are appealing candidate targets for risk and disease progression assessment. In this light, we explored the role of common single nucleotide polymorphisms (SNPs) in the main iron homeostasis genes and in the main lipoprotein transporter gene (APOE) in a cohort of 765 patients with dementia of different origin: Alzheimer's disease (AD) n = 276; vascular dementia (VaD), n = 255; mild cognitive impairment (MCI), n = 234; and in normal controls (n = 1086). In details, four genes of iron homeostasis (Hemochromatosis (HFE: C282Y, H63D), Ferroportin (FPN1: -8CG), Hepcidin (HAMP: -582AG), Transferrin (TF: P570S)), and the three major alleles of APOE (APOE2, APOE3, APOE4) were analyzed to explore causative interactions and synergies. In single analysis, HFE 282Y allele yielded a 3-fold risk reduction in the whole cohort of patients (P<0.0001), confirmed in AD and VaD, reaching a 5-fold risk reduction in MCI (P = 0.0019). The other iron SNPs slightly associated with risk reduction whereas APOE4 allele resulted in increased risk, reaching more than 7-fold increased risk in AD homozygotes (P = 0.001), confirmed to a lower extent in VaD and MCI (P = 0.038 and P = 0.013 respectively) as well as in the whole group (P<0.0001). Comparisons of Mini Mental State Examination (MMSE) among AD showed appreciable lowering in APOE4 carriers (P = 0.038), confirmed in the whole cohort of patients (P = 0.018). In interaction analysis, the HFE 282Y allele completely extinguished the APOE4 allele associated risk. Conversely, the coexistence in patients of a substantial number of iron SNPs accrued the APOE4 detrimental effect on MMSE. Overall, the analysis highlighted how a specific iron-allele burden, defined as different combinations of iron gene variants, might have different effects on cognitive impairment and might modulate the effects of established genetic risk factors such as APOE4. Our results suggest that established genetic risk factors might be affected by specific genetic backgrounds, making patients differently suited to manage iron accumulation adding new genetic insights in neurodegeneration. The recently recognized interconnections between iron and lipids, suggest that these pathways might share more than expected. We therefore extended to additional iron gene variants the newly proposed influencing mechanisms that HFE gene has on cholesterol metabolism. Our results have a strong translational potential promoting new pharmacogenetics studies on therapeutic target identification aimed at optimally tuning brain iron levels.
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Effect of Low-Dose Statins and Apolipoprotein E Genotype on Cerebral Small Vessel Disease in Older Hypertensive Patients: A Subgroup Analysis of a Randomized Clinical Trial.
Ji, T, Zhao, Y, Wang, J, Cui, Y, Duan, D, Chai, Q, Zhang, H, Liu, Z
Journal of the American Medical Directors Association. 2018;(11):995-1002.e4
Abstract
OBJECTIVES To investigate the effect of low-dose statins and apolipoprotein E (APOE) genotypes on cerebral small vessel disease (CSVD) to prevent CSVD in older hypertensive patients. DESIGN A subgroup analysis of a randomized clinical trial. SETTING Shandong area, China. PARTICIPANTS Hypertensive patients aged ≥60 years were recruited from April 2008 to November 2010. MEASUREMENTS Patients were randomly assigned to rosuvastatin (10 mg/day) or placebo groups. APOE genotypes were categorized as ε4 carriers and non-ε4 carriers. White matter hyperintensities (WMH), Fazekas scale, lacunes, and microbleeds were assessed. RESULTS After an average of intervention period of 61.8 months, WMH volume increased 1.45 ± 0.52 mL. There were 107 new-incident Fazekas scale ≥2, 65 new-incident lacunes, and 63 new-incident microbleeds. The increase in WMH volume was significantly lower in the rosuvastatin group than in the placebo group and was higher in APOE ε4 carriers than in non-ε4 carriers (all adjusted P < .001). The risk of new-incident Fazekas scale ≥2 was higher in the placebo group than in the rosuvastatin group (hazard ratio 2.150, 95% confidence interval 1.443-3.203; P < .001). APOE ε4 carriers were associated with an increased risk of new-incident Fazekas scale ≥2 compared with non-ε4 carriers (hazard ratio 1.973, 95% confidence interval 1.334-2.920; P = .001). There were no statistically significant differences in the risk of new-incident cerebral microbleeds between the rosuvastatin and placebo groups or between APOE ε4 carriers and non-ε4 carriers. There were no significant interactions between rosuvastatin use and APOE ε4 status regarding increased WMH volume (F = 1.020, P = .313) or for new-incident Fazekas scale ≥2 (P = .377), lacunes (P = .232), and microbleeds (P = .362). CONCLUSIONS/IMPLICATIONS Low-dose rosuvastatin is an effective and safe therapy for CSVD. The presence of APOE ε4 allele may not be able to predict rosuvastatin treatment outcomes for preventing and/or treating CSVD in older hypertensive patients.